The major objective of this R21 application is to explore the potential of two novel complimentary optical techniques, four-dimensional elastic light scattering fingerprinting (4D-ELF) and low-coherence backscattering (LEBS) spectroscopy, for minimally invasive diagnosis of pancreatic cancer without the need for interrogation of the pancreas. The work builds upon our development of these two optical techniques for in situ sensing of subtle histologically-undetectable changes in tissue nano/micro-architecture in early stages of carcinogenesis and completion of successful pilot human studies. Pancreatic cancer has one of the worst prognoses with an overall 5-year survival rate of <5%. The reason for this poor prognosis is that most pancreatic cancers are diagnosed only at a late, incurable stage. No current imaging techniques including CT, MRI, ultrasound and endoscopic cholangiopancreatography (ERCP) can reliably detect pancreatic precancerous or early cancerous lesions. Moreover, despite years of research, no clinically adequate molecular markers have been identified. Importantly, widespread pancreatic cancer screening by means of examination of the pancreatic duct (e.g., ERCP) is not feasible due to a very high risk of serious complications (approximately 20%) including pancreatitis (approximately 5%) caused by essentially any interrogation of the pancreatic duct including biopsy, fiber-optic evaluation, and brushing. Our objective is to develop a biophotonics approach for the early detection of pancreatic cancer without the need for interrogation of the pancreas. Our strategy is based on detection of the "field-effect" of pancreatic carcinogenesis, the proposition that the genetic/environmental milieu that results in a neoplastic lesion in a particular tissue site should be also detectable outside this location. This opens up a possibility to diagnose the risk of pancreatic neoplasia by examination of the duodenal periampullary mucosa, which can be readily accessed by means of existing upper endoscopy techniques without the risk of pancreatitis. We have obtained pilot data supporting the feasibility of this approach in the pancreas and other organs. [unreadable] [unreadable] [unreadable]